April 27, 2017
On April 27, 2017, the U.S. Food and Drug Administration expanded the indications of regorafenib (STIVARGA®, Bayer HealthCare Pharmaceuticals Inc.) to include the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.
Approval was based on an international, multicenter, randomized, double-blind, placebo-controlled trial of 573 patients with Child-Pugh A and Barcelona Clinic Liver Cancer Stage B or C HCC with documented disease progression following sorafenib. Patients were randomly allocated to receive regorafenib160 mg orally once daily plus best supportive care (BSC) or matching placebo plus BSC for the first 21 days of each 28-day cycle. Treatment continued until disease progression or unacceptable toxicity. The trial demonstrated a significant improvement in overall survival (HR=0.63, 95% CI: 0.50, 0.79, p<0.0001) with an estimated median overall survival for patients in the regorafenib arm of 10.6 months and 7.8 months for patients in the placebo arm. A statistically significant improvement was also demonstrated for progression-free survival (PFS) based on modified RECIST for HCC (HR=0.46, 95% CI: 0.37, 0.56, p<0.0001), with an estimated median PFS of 3.1 and 1.5 months in the regorafenib and placebo arms, respectively. The overall response rate, based on modified RECIST, was 11% in the regorafenib arm and 4% in the placebo arm.
The safety of regorafenib was evaluated in 1142 patients enrolled in randomized, placebo-controlled trials. The most common adverse reactions observed in 20% or more of patients taking regorafenib were pain, hand-foot skin reaction (HFSR), asthenia/fatigue, diarrhea, decreased appetite, hypertension, infection, dysphonia, elevated bilirubin, fever, mucositis, weight loss, rash, and nausea.
The recommended regorafenib dose is 160 mg (four 40 mg tablets) taken orally once daily after a low-fat meal for the first 21 days of each 28-day cycle.
Full prescribing information is available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/203085s007lbl.pdf.
FDA granted this application priority review and Orphan Drug Designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).
Pharmacist’s Applications to Practice
Regorafenib (Stivarga) for Hepatocellular Carcinoma with Disease Progression on Sorafenib Treatment
Authors: Andrew Thorne, PharmD
Health System Pharmacy Administration Resident
Matthew Arango, PharmD BCOP
Specialty Practice Pharmacist, Gastrointestinal Oncology
Ohio State University Wexner Medical Center
What is the potential role for regorafenib in the treatment of advanced hepatocellular carcinoma (HCC)?1-5
- Regorafenib is approved by the U.S. Food and Drug Administration (FDA) for the treatment of HCC in patients who experienced progression of disease on sorafenib.
- Previously no therapy beyond available clinical trials or supportive care has been recommended for this sorafenib-refractory setting. When compared to placebo, regorafenib demonstrated a survival benefit in these patients (10.6 months vs. 7.8 months).
- Regorafenib following sorafenib failure is appropriate only for patients who tolerated sorafenib doses greater than or equal to 400 mg/day because of the overlapping toxicity profiles of regorafenib and sorafenib.
What role can the pharmacist play in the management of patients on regorafenib?1,3
- Regorafenib is associated with many treatment-related adverse events, including hypertension, cardiovascular events, hepatotoxicity, hand-foot skin reaction, fatigue, and diarrhea.
- The prescribing information contains a boxed warning for hepatic failure. Monitor liver function tests every 2 weeks for the first 2 months of therapy and then monthly.
- Encourage patients to monitor blood pressure and look for signs of bleeding or thrombosis.
- Encourage patients to use a skin care routine, including regular use of sunscreen and application of moisturizing cream to the palms of hands and soles of feet.
- Regorafenib is associated with complications in the healing of wounds. Hold regorafenib for 2 weeks before planned surgery and do not resume until the wound is adequately healed.
- Dosing for regorafenib in HCC is the same as for other indications (colorectal cancer, gastrointestinal stromal tumor): 160 mg orally daily for the first 21 days of a 28-day cycle.
- It may be helpful to create a calendar for patients’ reference to keep them on schedule.
- Ensure that patients have the correct number of tablets (40 mg each) to complete each cycle.
- If patients experience toxicities, the dose may be reduced to 120 mg and then to 80 mg.
- Tablets expire 7 weeks after opening. For this reason, pharmacies will typically not dispense less than full 28-tablet bottles. Help patients understand that they may be given more tablets than they need per cycle.
- Counsel patients on the proper storage and handling of regorafenib: Tablets should be stored in the original bottle with desiccants in place. The patients should not cut, crush, or chew the tablets, and they should wash their hands after handling the tablets.
- No data support regorafenib use for HCC in patients with the following conditions (which were excluded from the registration trial):
- Child-Pugh class B or C, or bilirubin greater than 2 mg/dl
- prior liver transplant
- large untreated esophageal varices.
- Regorafenib should be taken with a low-fat meal (fewer than 600 calories and less than 30% fat). Examples of low-fat meals:
- Breakfast: cottage cheese, muffin or toast with butter or jam, and juice
- Lunch: turkey sandwich (turkey, white bread, mayonnaise, lettuce, tomato), large apple, and juice
- Dinner: spaghetti with marinara (meatless) sauce, salad with vegetables, and oil and vinegar salad dressing
- For patients with no insurance or inadequate insurance, assistance may be available through the Resources for Expert Assistance and Care Helpline (REACH) program at 1.866.639.2827.
- Regorafenib is metabolized by CYP3A4. Avoid concomitant usage of strong CYP3A4 inducers or inhibitors, including grapefruit juice.
- Hand-foot skin reaction and liver toxicity were seen more often in Asian patients on regorafenib.
- Stivarga [package insert]. Whippany, NJ: Bayer; 2017.
- Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESOURCE): a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet 2017;389:56-66.
- Regorafenib. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed July 10, 2017.
- Hepatobiliary Cancers. Version 2.2017. National Comprehensive Cancer Network. Available at: https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf. Accessed July 15, 2017.
- Bayer. Your guide to taking Stivarga. Available at: www.stivarga-us.com/helpful-resources/patient-starter-kit/patient-brochure/. Accessed July 10, 2017.
- Bayer. Helping you get and pay for your medicine. Available at: www.stivarga-us.com/getting-and-paying/REACH/. Accessed July 26, 2017